2. Academic Validation
  3. Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration

Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration

  • Nat Chem Biol. 2017 Sep;13(9):994-1001. doi: 10.1038/nchembio.2442.
Haiming Jiang 1,  Rong Deng 1 2,  Xiuyan Yang 1,  Jialin Shang 1,  Shaoyong Lu 1,  Yanlong Zhao 1,  Kun Song 1,  Xinyi Liu 1 3,  Qiufen Zhang 1 3,  Yu Chen 4,  Y Eugene Chinn 5,  Geng Wu 6,  Jian Li 7,  Guoqiang Chen 1 5,  Jianxiu Yu 1 2,  Jian Zhang 1 3
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
  • 2 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
  • 3 Medicinal Bioinformatics Center, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, China.
  • 5 Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
  • 6 State Key Laboratory of Microbial Metabolism, Shanghai Jiao-Tong University, Shanghai, China.
  • 7 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
PMID: 28759015 DOI: 10.1038/nchembio.2442
Abstract

The binding of adenomatous polyposis coli (APC) to its receptor Asef relieves the negative intramolecular regulation of Asef and leads to aberrant cell migration in human colorectal Cancer. Because of its crucial role in metastatic dissemination, the interaction between APC and Asef is an attractive target for anti-colorectal-cancer therapy. We rationally designed a series of peptidomimetics that act as potent inhibitors of the APC interface. Crystal structures and biochemical and cellular assays showed that the peptidomimetics in the APC pocket inhibited the migration of colorectal cells by disrupting APC-Asef interaction. By using the peptidomimetic inhibitor as a chemical probe, we found that CDC42 was the downstream GTPase involved in APC-stimulated Asef activation in colorectal Cancer cells. Our work demonstrates the feasibility of exploiting APC-Asef interaction to regulate the migration of colorectal Cancer cells, and provides what to our knowledge is the first class of protein-protein interaction inhibitors available for the development of Cancer therapeutics targeting APC-Asef signaling.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P2269
    Anti-cancer Agent